McGee A W, Topinka J R, Hashimoto K, Petralia R S, Kakizawa S, Kauer F W, Aguilera-Moreno A, Wenthold R J, Kano M, Bredt D S
Department of Physiology and Programs in Biomedical Sciences and Neuroscience, University of California at San Francisco School of Medicine, San Francisco, California 94143-0444, USA.
J Neurosci. 2001 May 1;21(9):3085-91. doi: 10.1523/JNEUROSCI.21-09-03085.2001.
Membrane-associated guanylate kinases (MAGUKs) are abundant postsynaptic density (PSD)-95/discs large/zona occludens-1 (PDZ)-containing proteins that can assemble receptors and associated signaling enzymes at sites of cell-cell contact, including synapses. PSD-93, a postsynaptic neuronal MAGUK, has three PDZ domains that can bind to specific ion channels, including NMDA delta2 type glutamate receptors, as well as Shaker and inward rectifier type K(+) channels, and can mediate clustering of these channels in heterologous cells. Genetic analyses of Drosophila show that MAGUKs play critical roles in synaptic development because mutations of discs large disrupt the subsynaptic reticulum and block postsynaptic clustering of Shaker K(+) channels. It is uncertain whether MAGUKs play an essential role in the development of central synapses. There are four neuronal MAGUKs with overlapping expression patterns in the mammalian brain; however, we find PSD-93 is the only MAGUK expressed in cerebellar Purkinje neurons. Therefore, we targeted disruption of PSD-93 in mouse. Despite the absence of MAGUK immunoreactivity in Purkinje neurons from the knock-outs, these mice have no structural or functional abnormality in cerebellum. Both the dendritic architecture and the postsynaptic localization of PSD-93 interacting proteins remain intact at light and electron microscopic levels in the knock-outs. Postsynaptic Purkinje cell responses, monosynaptic climbing fiber innervation, and cerebellar-dependent behaviors are also normal. Our data demonstrate that MAGUK proteins of the PSD-93/95 family are not essential for development of certain central synapses but may instead participate in specialized aspects of synaptic signaling and plasticity.
膜相关鸟苷酸激酶（MAGUKs）是富含突触后致密区（PSD）-95/盘状大蛋白/紧密连接蛋白1（PDZ）的蛋白质，可在细胞间接触部位（包括突触）组装受体和相关信号酶。PSD-93是一种突触后神经元MAGUK，具有三个PDZ结构域，可与特定离子通道结合，包括NMDA δ2型谷氨酸受体以及震颤型和内向整流型K(+)通道，并可介导这些通道在异源细胞中的聚集。果蝇的遗传分析表明，MAGUKs在突触发育中起关键作用，因为盘状大蛋白的突变会破坏突触下网状结构并阻断震颤型K(+)通道的突触后聚集。目前尚不确定MAGUKs在中枢突触发育中是否起重要作用。在哺乳动物大脑中有四种神经元MAGUKs，其表达模式相互重叠；然而，我们发现PSD-93是小脑浦肯野神经元中唯一表达的MAGUK。因此，我们在小鼠中靶向破坏PSD-93。尽管敲除小鼠的浦肯野神经元中没有MAGUK免疫反应性，但这些小鼠的小脑没有结构或功能异常。在敲除小鼠的光镜和电镜水平上，PSD-93相互作用蛋白的树突结构和突触后定位均保持完整。突触后浦肯野细胞反应、单突触攀缘纤维支配以及小脑依赖行为也均正常。我们的数据表明，PSD-93/95家族的MAGUK蛋白对于某些中枢突触的发育并非必不可少，而是可能参与突触信号传导和可塑性的特殊方面。
